Human diseases caused by deficiencies of protein function collectively represent a major unmet medical need. We are thus pioneering the development of Molecular Prosthetics, small molecules that mimic the functions of missing proteins. We hypothesize that the robust nature of living systems will permit imperfect small molecule mimics to be sufficient for restoration of physiology in many cases. Our preliminary studies of natural products that perform protein-like functions in yeast and human epithelia are highly encouraging. These studies further link this tolerance for imperfection to molecular bionic systems in which the small molecules collaborate with compensatory networks of proteins. Building on this strong foundation of preliminary results, we plan to extensively probe and optimize the capacity for small molecules to act as prostheses on the molecular scale and thereby treat cystic fibrosis, microcytic anemia, and asthma. This project will further lay the foundation for applying this same approach to many other currently incurable human diseases caused by missing proteins. Natural products serve as exceptional starting points for the development of these and many other types of human therapeutics, but synthesis of these complex molecules and their derivatives often represents a major bottleneck. We will thus pursue in parallel more general and automated synthetic access to such compounds. Over the past decade we have developed an increasingly general small molecule synthesis platform based on the iterative assembly of bifunctional MIDA boronate building blocks. This platform is now extensively used worldwide and enabled us to develop less toxic derivatives of the clinically vital, but highly toxic, antifungal amphotericin B that are now being advanced toward clinical trials. We also recently created a machine that automates this type of synthesis. Building on all of this momentum, we now plan to launch The Natural Productome Project targeting general and automated synthetic access to most natural products. Synergizing with complementary efforts by many other research groups worldwide, we will determine the minimum number of building blocks from which most natural products can be made, pursue new methods to make and iteratively couple these building blocks together, and develop generalized biomimetic strategies to transform building block- derived linear precursors into complex polycyclic natural product-like frameworks. Similar to The Human Genome Project, The Natural Productome Project will serve to rally the global scientific community to collectively achieve a major advance with the potential to transform science and medicine.